Multiple sclerosis (MS) is characterized by immunological and inflammatory changes that contribute to demyelination of nerve fibers and neuronal cell death. Although MS is a prototypic primary demyelinating disease, increasing evidence indicates that neuronal degeneration also occurs in MS, contributing to the acquisition of nonremitting clinical deficits. The main features of MS can be reproduced in an animal model, experimental autoimmune encephalomyelitis (EAE). Drugs that reduce the activity of the NMDA or Kainate subtypes of glutamate receptors (NMDAR, KAR), which are expressed both on neurons and oligodendrocytes, suppress EAE. In this proposal, a novel cyclic peptide compound, CN2097, will be tested for its ability to ameliorate MS-like symptoms and pathology. This compound binds the PDZ-domain of the postsynaptic density protein, PSD-95, disrupting its interaction with KAR and NMDAR subtypes. PSD-95 plays a critical role in kainate-mediated excitotoxicity by acting as a molecular scaffold to link KARs to JNK activation. NMDA-induced cell death is linked to the association of PSD-95 with CaMKII, nNos and other primary cell death signaling proteins. In an in vivo retinal toxicity model CN2097 completely blocked NMDA-induced cell death. Aim 1 will examine the signaling pathways and the effects of this compound on attenuating kainate-induced cell death in an in vivo retinal toxicity model, as well as in cortical neurons and retinal oligodendrocytes in vitro. Aim 2 will determine whether CN2097 can increase the survival and function of optic and spinal cord nerves using a MS animal model, myelin oligodendrocyte glycoprotein-experimental autoimmune encephalomyelitis (MOG-EAE), that emulates MS. Testing the neuroprotective effects of CN2097 in EAE rats is of clinical relevance in slowing or reversing MS-related neurological disability. We hypothesize that this PDZ-domain inhibitor will improve the tolerance for the treatment because it does not appear to interfere with normal NMDA or AMPA receptor activity, while ameliorating the disease related excitotoxic damage. PUBLIC HEALTH RELEVANCE: Recent studies show that glutamate receptors, which are important in transmitting signals from one nerve cell to another, also increase sensitivity to the death of neurons and myelinating oligodendrocytes in multiple sclerosis. We have synthesized a series of high affinity compounds that completely prevent neuronal death and are predicted to improve the tolerance for treatment because they do not affect the ability of glutamate receptors to signal between nerves, while preventing the disease related damage. The central goal of this research grant is to better understand the action of our most promising compound (CN2097) and to determine its potential as a new therapeutic approach for treating multiple sclerosis.